p62 condensates are a hub for proteasome-mediated protein turnover in the nucleus

The ability to selectively degrade cellular components ranging from proteins to large complexes and organelles is essential for cellular quality control. Failure leads to accumulation of unwanted material that gives rise to neurodegeneration, cancer, and infectious diseases (1). Two main degradative pathways have evolved: the ubiquitin–proteasome system (UPS) and autophagy. While the selective degradation of soluble proteins is normally conducted by the UPS, which needs unfolding of its substrates to traverse through the narrow openings of the proteasome, macroautophagy (hereafter termed autophagy) is able to sequester cytosolic cargo into a newly synthesized double-membrane compartment, called the autophagosome, that later fuses with the vacuole/lysosome for degradation. This empowers autophagy to degrade bulky cargo such as invading pathogens, protein aggregates, or damaged/disused organelles. Both pathways are essential components of the proteostasis network. In PNAS, Fu et al. (2) uncover a role of the protein p62 in orchestrating proteasomal protein turnover in the nucleus (Fig. 1). Fig. 1. Depiction of the functional roles of p62 within the cell. The cytoplasmic pool of p62 serves as a cargo receptor for the recognition of ubiquitylated protein aggregates by selective autophagy. Here, p62 targets ubiquitylated misfolded proteins and phase separates into condensates through multivalent interactions established with multiple Ubs linked in chains. The nuclear pool of p62 also forms condensates in a similar fashion as its cytosolic counterpart but recruits the UPS for efficient removal of nuclear proteins. The local p62-dependent concentration of the UPS members facilitates efficient removal of its substrates. The multifunctional protein p62/SQSTM1 plays an important role in targeting ubiquitin (Ub)-modified proteins to either the proteasome or the autophagy machinery (3). Ubiquitylated proteins are captured by binding to the C-terminal Ub-associated (UBA) domain of p62 (4). To couple cargo recognition with autophagosome biogenesis, p62 interacts with lipidated LC3 via its LC3 interacting region (LIR). … [↵][1]1To whom correspondence may be addressed. Email: florian.wilfling{at}biophys.mpg.de. [1]: #xref-corresp-1-1